title: Modulation of αvβ₃- and α₅β₁-integrin-mediated adhesion by dehydro-β-amino acids containing peptidomimetics.
abstract: A novel class of low molecular weight ligands of αvβ₃ and α₅β₁ integrins, that possess a dehydro-β-amino acid as conformationally constrained core, linked to the pharmacophoric moieties mimicking the RGD recognition sequence, have been synthesized through a very simple protocol. Cell adhesion assays and integrin-mediated signaling activation experiments suggested a good affinity of these compounds toward both integrin receptors. Moreover, further elongation with two glycine units allowed to obtain an excellent dual inhibitor. Structural models for αvβ₃ integrin-ligand binding confirmed that the dehydro-β-amino derivatives are able to act as an electrostatic clamp by establishing several stabilizing interactions with the receptor.
authors.affiliation: Department of Chemistry G.Ciamician, University of Bologna, Via Selmi 2, 40126 Bologna, Italy. alessandra.tolomelli@unibo.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tolomelli
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Angelo
authors.initials: A
authors.lastname: Viola
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Troisi
authors.forename: Samantha Deianira
authors.initials: SD
authors.lastname: Dattoli
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
authors.forename: Eusebio
authors.initials: E
authors.lastname: Juaristi
authors.forename: Margarita
authors.initials: M
authors.lastname: Escudero
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D039081:Integrin alpha5beta1 / Q000737:chemistry / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020014:K562 Cells; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005353:Fibronectins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D057786:Peptidomimetics; C047981:arginyl-glycyl-aspartic acid; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cell adhesion; Dehydro-β-amino acids; Drug discovery; Peptidomimetic; Signaling